tbuckley/cabot-search huggingface dataset:
Genomic profiling to provide new treatment opportunities in ampullary carcinoma.
Authors: Carles Fabregat Franco, Florian Castet, Nadia Saoudi Gonzalez, Gloria Castillo, Daniel Acosta Eyzaguirre, Maria Teresa Salcedo, Helena Verdaguer, Teresa Macarulla
Journal: Journal of Clinical Oncology (2023)

582 Background: Ampullary carcinoma (AC) is a rare heterogeneous group of diseases with an abysmal prognosis. Treatment options are limited, and the molecular landscape of this disease and its therapeutic implications have been incompletely explored. Here, we aim to provide a clinical and genomic characterization of AC and explore opportunities for precision oncology. Methods: Patients diagnosed with AC and treated at a single tertiary institution between 2010 and 2022 were reviewed. Molecular profiles were analyzed by applying an in-house exome-targeted panel or the FoundationOne CDx panel. Gene mutations were categorized into molecular pathways and potentially targetable alterations were classified according to the ESCAT scale. Overall survival (OS) and disease-free survival (DFS) were estimated by using the Kaplan-Meier method. Results: We included 64 patients with a median age of 66 years, 51.6% were women, most were classified as pancreatobiliary tumours (PB, 58.3%), followed by intestinal (INT, 33.3%) and mixed histologies (8.3%). 18.8%, 23.4%, 32.8% and 25.0% of the patients were diagnosed at stage I, II, III and IV, respectively. 81.2% of the patients were treated with surgery. The INT subtype was enriched in WNT pathway alterations (28.6 vs 6.2%, p=0.02) and showed a non-significant enrichment in the apoptotic pathway (57.1 vs 34.4%, p=0.08). Conversely, BP showed a non-significant enrichment in HRR pathway alterations (16.7 vs 54.5%, p=0.3). The frequency of KRAS mutations were similar in both subtypes (38.1 vs 37.5%). Potentially actionable molecular alterations were found in 46.7% of the patients (9 ERBB2, 8 HRD, 8 PI3KCA, 2 MSI, 2 BRAF, 2 PTEN and 1 KRAS G12C). Importantly, KRASwt tumours were enriched in potentially targetable alterations (ESCAT I-IIIA), including 20% ERBB2 amplification/mutations, 6% MSI and 3% BRCA1. 6 patients received matched targeted therapies during their disease course, 66% of which responded and 100% stable disease, with a median TTD of 7 months. Conclusions: More than 45% of AC harbor potentially targetable genomic alterations that may provide novel therapeutic opportunities and enhance personalized medicine in this rare disease entity.
Bleeding and thrombotic events in patients with colorectal cancer treated with bevacizumab and receiving novel oral anticoagulants and antiplatelet medications.
Authors: Shinji Rho, Chris Wang, Seyed Hamed Hosseini Dehkordi, Jerod J Sears, Zishuo Ian Hu
Journal: Journal of Clinical Oncology (2023)

104 Background: Bevacizumab is a humanized monoclonal VEGF antibody given in combination with fluorouracil-based chemotherapy for metastatic colorectal cancer (mCRC). Many patients with mCRC also have cardiovascular comorbidities requiring anticoagulation or antiplatelet therapy. The bleeding and thrombotic event rates in the setting of concurrent novel oral anticoagulants (NOACs) and bevacizumab treatment in patients with mCRC remain unclear. Methods: 462 patients with mCRC at Barnes-Jewish Hospital were identified between December 1, 2016 and December 1, 2021 and screened for concurrent treatment with bevacizumab and anticoagulant or antiplatelet therapy. Demographic and clinical information was extracted by electronic chart review. Results: 21 patients were identified who received bevacizumab and either apixaban or rivaroxaban for mCRC treatment. Aspirin was prescribed in some of these patients within 3 years of starting apixaban or rivaroxaban. Of the 13 patients who had no history of aspirin prescription, 9 were given apixaban, and 4 were given rivaroxaban while on bevacizumab. 44.4% of the patients who received apixaban experienced bleeding. All these events were epistaxis, and only 25% of the cases resulted in any treatment discontinuation. 75% of the patients who received rivaroxaban experienced bleeding events, which 33.3% of the time resulted in discontinuation of either rivaroxaban or bevacizumab. We also looked at 8 patients who had received aspirin in the last three years: 7 patients were on apixaban, and one was on rivaroxaban while on concomitant aspirin and bevacizumab. 28.6% of the patients who received apixaban with bevacizumab and aspirin experienced an adverse bleeding event that resulted in some form of treatment discontinuation. Meanwhile, the patient who received rivaroxaban with bevacizumab and aspirin experienced a bleeding event that resulted in discontinuation of a medication. No patient experienced any adverse thrombotic events. Conclusions: Patients with mCRC treated with bevacizumab and apixaban with no history of prior aspirin use within three years have a relatively low risk of developing bleeding events that warrant treatment discontinuation. The addition of NOAC to bevacizumab therapy does not appear to increase the risk of adverse thrombotic events.
Efficacy and safety of neoadjuvant preoperative short-course radiation followed by envafolimab plus CAPEOX in microsatellite stable (MSS)/mismatch repair proficient (pMMR) locally advanced rectal cancer.
Authors: Sheng Dai, Fei Wang, Yanbin Shen, Liming Shi, Lingna Xu, Chuanxi Lai, Feixiang Zhang, Kangke Zhang, Dengyong Xu, Lina Shan, Gaoyang Cao, Da Wang, Weifeng Lao, Xiaonan Sun, Xuefeng Huang
Journal: Journal of Clinical Oncology (2023)

134 Background: Chemoradiation is the standard neoadjuvant treatment for locally advanced rectal cancer. Microsatellite stable (MSS)/ mismatch repair proficient (pMMR) rectal cancer rarely responds to immune checkpoint inhibitor monotherapy, but combination with chemoradiation may improve sensitivity of MSS/pMMR tumors by inducing immune-stimulatory effects. Therefore, we aimed to investigate the efficacy and safety of patients treated with neoadjuvant preoperative short-course radiation followed by envafolimab plus CAPEOX for MSS/pMMR locally advanced rectal cancer. Methods: This is an open-label, single-center, phase ¢ò study. Patients (pts) with locally advanced rectal adenocarcinoma with MSS/pMMR were eligible. MMR protein expression was tested by immunohistochemistry (IHC) £¬and MSI status was confirmed by NGS (next generation sequencing). All pts included in this study underwent neoadjuvant short-course radiation (total dose of 5¡Á5Gy) in the first week after enrollment, then followed by 6 cycles of envafolimab (anti-PD-L1 inhibitor,150mg, d1, subcutaneous injection, QW) plus 2 cycles of CAPEOX in the next six weeks, and subsequently underwent total mesorectal excision (TME) in the ninth week. The primary endpoint is pathological complete response rate. Secondary endpoints include tumor regression grade (TRG), 3 year disease free survival, overall survival, toxicity, and quality of life (QoL). Results: This study intends to recruit 32 pts, and a total of 21 pts were enrolled from January 2022 to September 2022. Overall median age was 67 (42-79) years. 12 pts completed study designed treatment protocol (envafolimab plus CAPOX) followed with TME procedures, and 9 pts are still undergoing neoadjuvant treatment. All 12 pts achieved major partial response (MPR) evaluated by diffusion-weighted magnetic resonance imaging (DW-MRI), and 8 pts (8/12,76.6%) achieved pCR. During neoadjuvant treatment period, 20 pts (20/21, 95.2%) presented with treatment-related AEs (TRAEs) of any grade, 18 pts (18/21, 85.7%) had grade 1-2 and one each pts had grade 3 and 4 thrombocytopenia (2/21, 9.5%). The most common TRAEs were sensation of rectal tenesmus. Conclusions: Neoadjuvant preoperative short-course radiation followed by envafolimab plus CAPEOX in MSS/pMMR locally advanced rectal cancer achieved a promising pathologic response. Meanwhile, this combination neoadjuvant therapy is safe and worthy of application to clinical practice. (Funded by Sir Run Run Shaw Hospital Zhejiang University School of Medicine.) Clinical trial information: NCT05216653 .
Adult BMI change over time and risk of colorectal adenoma.
Authors: Parker Jayce Holum, Chelsea Palmer, Xiangqing Sun, Samyukta Venkatesh, Matthew Devall, Gregory Cooper, Steven M. Powell, Cynthia Yoshida, Li Li
Journal: Journal of Clinical Oncology (2023)

68 Background: Obesity and adult weigh gain are established risk factors for colorectal cancer (CRC). Few studies have investigated the association between adult body weight change over time and risk of colorectal adenoma. We hypothesize adult BMI change over time is associated with risk in the development of colorectal adenomas. Methods: We tested this hypothesis in 2,993 patients undergoing screening colonoscopy from 2007–2017. Weight at age 20, 30, 40, and 50 were self-reported via computer assisted personal interviews. Height and weight at recruitment were measured at the time of colonoscopy exam. BMI (kg/m 2 ) change was calculated as the difference of BMI at recruitment from the BMI estimate for each of the age periods. Results: Of the 2,993 patients, 984 had pathologically confirmed diagnosis of colon adenoma. Multivariate logistic regression adjusted for potential confounders and BMI at recruitment showed statistically significant increase of risk of adenoma with increase of BMI since age 30, age 40, and age 50. Compared to those with BMI change of less than 5, the ORs for those with BMI gain of 5-10 and ≥10 were: 1) 1.16 (0.92-1.46) and 1.48 (1.08-2.03) respectively for change from age 30 (p trend = 0.05); 2) 1.11 (0.87-1.43) and 1.60 (1.09-2.35) respectively for change from age 40 (p trend = 0.05); and 3) 1.36 (0.95-1.94) and 2.95 (1.33-6.90) respectively for change from age 50 (p trend = 0.01). Stratified analysis did not reveal noticeable gender differences. Conclusions: Large adult weight gain over time is an independent risk factor for colorectal adenoma. Our results suggest maintaining healthy body weight throughout adulthood is an important preventive measure against the development of early colorectal neoplasia. [Table: see text]
Source of funding and enrollment disparities in the inclusion of minorities in colorectal clinical trials: A systematic review and meta-analysis.
Authors: Ahsan Ayaz, Syed Arsalan Ahmed Naqvi, Mahnoor Islam, Waleed Ikram, Umar Raza, Anum Riaz, Kaneez Zahra Rubab Khakwani, Hafsah Ijaz, Bassam Bassam Sonbol, Zhaohui Jin, Irbaz Bin Riaz
Journal: Journal of Clinical Oncology (2023)

23 Background: Identification of factors associated with enrollment disparities in clinical trials can narrow cancer care inequities. Funding source can influence minority representation in clinical trials. Therefore, we aimed to assess the impact of funding sources on enrollment disparities in colorectal (CRC) clinical trials. Methods: CRC phase II/III randomized controlled trial (RCTs) identified through MEDLINE and EMBASE from each database’s inception through 2022 were considered eligible. Trial level enrollment incidence ratios (EIR) were computed; defined as the ratio of trial proportions of a gender, age, or racial/ethnic subgroup category and the global incidence in the corresponding gender/age subgroup (from the global burden of disease database), or the US-population-based incidence in the corresponding racial/ethnic subgroup (from SEER 21 database). EIRs were then meta-analyzed using a random-effects model for each funding source category (US- government, industry, others). Temporal trends were analyzed using a univariate meta-regression. Results: Using data from 287 RCTs, women were significantly under-represented in the industry sponsored trials (EIR: 0.85 [95% CI: 0.83 - 0.88]) but not in US-government sponsored trials (0.92 [0.84-1.00]). A total of 87 RCTs reported age proportions; older adults (above 65 years) were significantly under-represented in the industry sponsored (0.84 [0.74-0.96]) and as well as in US-government sponsored CRC trials (0.52 [0.44-0.61]). Only 56 and 15 trials reported race and ethnicity, respectively. Limited data on racial/ethnic enrollment revealed significant under-representation of Black (0.45 [0.36 -0.57]) and Hispanic (0.45 [0.31-0.66]) patients across industry sponsored CRC trials. In contrast, no significant disparity was observed in the inclusion of Asian race in the industry sponsored trials. The number of US-government sponsored trials reporting racial/ethnic subgroups were small ( &lt; 10) which precluded any meaningful statistics. Trends show that the representation of women has improved ( P: 0.02) while the representation of Black ( P: 0.007) and Hispanic patients ( P: 0.04) has worsened over the last three decades in industry sponsored CRC trials. Conclusions: The reporting of race/ethnicity is suboptimal in CRC trials especially in those sponsored by US government. Older adults may be under-represented regardless of funding source. Women, Blacks and Hispanics may be under-represented in industry sponsored CRC clinical trials. While representation of women appears to be improving, representation of Black and Hispanic patients has worsened in industry sponsored CRC clinical trials over the last three decades.
Anlotinib plus PD-1 inhibitors as chemo-free therapy in advanced or metastatic esophageal cancer: Updated results from a retrospective real-world study.
Authors: Yonggui Hong, Tao Wu, Ping Lu, Zhiwei Chang, Wei Liang, Guifang Zhang, Yongjing Tian, Junsheng Wang
Journal: Journal of Clinical Oncology (2023)

310 Background: Compared to standard chemotherapy, immune checkpoint inhibitors monotherapy and combined with chemotherapy regimens have been shown significant benefits for patients with advanced or metastatic esophageal cancer in both second-line and first-line treatment, respectively. Anlotinib was an effective second-line monotherapy for esophageal squamous cell carcinoma in China and the combination of anlotinib and immunotherapy might be a promising strategy. The study aimed to investigate the efficacy and safety of anlotinib plus PD-1 inhibitors during the treatment of esophageal cancer in the real world setting. Methods: This is a multicenter real-world study in patients with unresectable locally advanced, recurrent or metastatic esophageal cancer, who would benefit from anlotinib plus a PD-1 inhibitor under the doctor's evaluation. The enrolled patients received treatment according to physicians. The primary endpoint was PFS, and secondary endpoints included ORR, DCR and OS. The response to treatment was evaluated according to RECIST version 1.1. In addition, adverse events were evaluated by CTCAE v5.0. Results: Between May 2020 and Sep 2022, 207 pts were enrolled. 109 comprised the evaluable population. In the full analysis set, 203 patients were squamous cell and 4 were adenocarcinoma histology. 137 of 207 (66.2%) pts were male. 44(21.3%) had an ECOG performance status of 0, 136 (65.7%) status of 1 and 27 (13.0%) status of ≥2. 47 pts had previously used anti-PD-1/PD-L1 antibody or vascular targeting drugs, of which 8 cases had combined anti-PD-1/PD-L1 antibody and vascular targeting drugs. Among the 109 evaluable pts, 17 (15.6%) pts received first-line therapy, 64 (58.7%) second-line and 28(25.7%) third &amp; above line. Of which, 5 patients achieved complete response (CR), 32 pts partial response (PR), 62 pts stable disease (SD), illustrating an ORR of 34.0% (95%CI 25.1-43.6) and a DCR of 90.8%(95%CI 83.8-95.5). In the first line therapy, ORR was 47.1% and DCR was 88.2%. In the second line therapy, ORR was 32.8% and DCR was 96.9%. In the third &amp; above line, ORR with 28.6% and DCR with 78.6% were observed. Median PFS was not reached, 6m-PFS rate was 87.9%. Treatment related adverse events (TRAEs) were reported in 55 pts (50.5%). 6 patients had grade 3 or more TRAEs. Conclusions: Anlotinib plus PD-1 inhibitors for advanced or metastatic esophageal cancer demonstrated a promising clinical benefit and a manageable safety profile. Further investigation in larger cohorts and even randomized controlled studies is warranted. Clinical trial information: NCT04966611 .
Durvalumab (MEDI 4736) with extended neoadjuvant regimens in rectal cancer: A randomised phase II trial (PRIME-RT).
Authors: Campbell SD Roxburgh, Catherine Ruth Hanna, Janet Graham, Mark P. Saunders, Leslie M. Samuel, Nicholas James MacLeod, Lynsey Devlin, Joanne Edwards, Lily Hillson, Ross K McMahon, Leia Ashleigh Jones, Caroline Kelly, Liz-Anne Lewsley, Paula Morrison, Peter Atherton, Nicola Walker, Jacqueline Gourlay, Ellie Tiplady, Richard Adams, Sean Michael O'Cathail
Journal: Journal of Clinical Oncology (2023)

TPS282 Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but many patients still die from distant disease. There is increasing recognition that with neoadjuvant treatment some patients achieve a complete response and may avoid surgical resection. PRIME-RT tests the inclusion of neoadjuvant immunotherapy with the aim of enhancing complete response rates, improving stoma-free survival and reducing distant relapse. Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients are randomised to Arm A: short course radiotherapy (25 Gray in 5 fractions) with concomitant durvalumab, followed by durvalumab and FOLFOX chemotherapy, or Arm B: long course chemoradiotherapy (50 Gray to primary tumour, 45 Gray to elective nodes, in 25 fractions with capecitabine) with concomitant durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Bio-specimens including serial tumour biopsies and peripheral blood samples are collected prior to, during, and following treatment to explore the molecular and immunological factors underpinning treatment response. The main trial will recruit up to 42 patients and commence after a safety run-in which is recruiting patients with metastatic disease. After opening in January 2021, the four patients completed the safety run in and the main trial commenced in March 2022. The trial is currently open across 5 UK sites. Up to date recruitment details will be provided at the time of presentation but at the time of writing this is ahead of target. Early recruitment to PRIME-RT has shown that adding immunotherapy in the neoadjuvant setting for LARC is feasible. Furthermore, on treatment biospecimen collection is also feasible across multiple sites. The expectation is that the trial will provide efficacy and safety information which allows the optimal treatment approach to be tested within a larger phase clinical trial. Core funding (Glasgow CRUK CTU) and trial-specific funding (Astrazeneca). Clinical trial: NCT04621370; ISRCTN18138369. Clinical trial information: ISRCTN18138369 .
Phase II study of TAS-OX (TAS-102 and oxaliplatin) plus bevacizumab for late-line colorectal cancer.
Authors: Howard S. Hochster, Hao Liu, Lyudmyla Derby Berim, Kristen Renee Spencer, Pat Gulhati, Manda DiRubbo, Seth D. Cohen, Patrick Lee, Stuart P. Leitner, Delia Radovich, Christian Misdary, Christian Perez, Sutirtha Datta, Andrea Gonzalez, Tracie Saunders, Patrick M Boland
Journal: Journal of Clinical Oncology (2023)

144 Background: TAS-102 (trifluridine/tipiracil) is a novel oral antimetabolite for late line metastatic colorectal cancer (CRC) approved in 2018. Many patients are treated early in their course with oxaliplatin (OX), particularly adjuvant, and may benefit from re-treatment. In this trial we combine the typical late line use of TAS with OX (BEV [bevacizumab] added at investigator discretion) with goal of improved response. Methods: Eligibility included measurable CRC previously treated with all approved drugs per TAS package insert (irinotecan, oxaliplatin, 5FU, anti-VEGF, anti-EGF) as appropriate, PS = 0-1, labs within usual range, neuropathy &lt; grade 2, ability to take oral meds, appropriate contraception. If no contraindication to BEV, this could be added at patient. TAS was dosed at 35 mg/m2 days 1-5 with OX 85/m2 d1 every 14 days (and BEV 5 mg/kg, if given). All supportive care was allowed including growth factors. Results: 47 patients (pts, median age 55) were enrolled in a Simon mini-max design, including 45% female, 21% black, 11% Asian, 11% Hispanic and 5% mixed. 26 pts received BEV. For the first 40 pts, 385 cycles were given (mean = 7 cycles, median 8) with 18 pts (45%) requiring dose reductions (1 dose reduction = 9 pts, 2 = 6, 3 = 3), and 9 receiving (peg)/filgrastim. Toxicities leading to SAEs included gr 3 heme (2), heart failure, abd pain/n/v (6), sepsis (2), urinary (4); and related gr 3 included one gr 3 vomiting and one gr 3 neutropenia. Independently reviewed RECIST Response (N = 32) included PR 2(6%), SD 23 (72%), PD 7 (22%). Mean TTP was 4.5 m (median 4, range 1 – 18) with 9 (28%) pts more than 6 months. Conclusions: In patients with late-line CRC and candidates for TAS (trifluridine/tipiracil), treatment with TAS plus OX is both well tolerated and active. RR is higher than single agent and 78% (95% CI, 60-91%) of patients had stable disease or response, with 60% receiving 8 or more cycles. Randomized trials comparing to single agent TAS are warranted in this setting. Clinical trial information: NCT04294264 .
Emergence of <i>RAS </i>mutations in <i>RAS</i> wild type metastatic colorectal cancer patients receiving cetuximab as first-line treatment: A prospective study.
Authors: Hsiang-Lin Tsai, Jaw-Yuan Wang
Journal: Journal of Clinical Oncology (2023)

38 Background: Metastatic colorectal cancers (mCRC) with wild-type KRAS are often sensitive to anti-EGFR, but occasionally develop resistance within treatment. A major limitation of treatment that selectively target kinase signaling pathways is the emergence of secondary resistance. However, interlink between emergence of KRAS mutations and secondary resistance to anti-EGFR remains to be further elucidated. In this study, we investigate evolutional changes of KRAS mutations through liquid biopsy in mCRC patients under cetuximab-treatment. Methods: Patients enrolled to receive cetuximab plus FOLFIRI or mFOLFOX6 as first-line treatment. The treatment was anticipated to be continued until disease-progression, intolerable toxic effects, or withdrawal of consent. Blood samples from patients were collected before and every three months during the cetuximab-treatment, and were required at disease-progression. These samples were evaluated for KRAS mutation using the MassARRAY platform. The primary endpoint was the percentage of patients with KRAS mutation detected during treatment. The clinical outcomes of these patients with emergence of mutant KRAS were further analyzed. Results: 108 mCRC cetuximab-treated patients, 95 patients combined with FOLFIRI and 13 patients with mFOLFOX6, were enrolled between January 2018 and June 2020. The median follow-up time was 26.5 months [interquartile range (IQR), 17.0-37.0 months]. The median duration of cetuximab-treatment was 9.0 months (IQR, 5.0-12.0 months). The percentage of detected KRAS mutations during cetuximab-treatment was 9.26%. Median emergent time of KRAS mutation from initial treatment was 5.0 months (IQR, 2.0-7.5 months). The median duration from KRAS mutation to disease-progression was 3.0 months (IQR, 2.0-6.5 months). The median progression-free survival (PFS) and overall survival (OS) of emergent RAS mutations and RAS wild-type were 8.0 versus 19.0 months ( P = 0.002) and 20.0 versus not-reach months ( P = 0.027), respectively. Conclusions: The identified KRAS mutations as a predictor of early resistance during cetuximab therapy, indicating that emergence of KRAS-mutant clones can be detected 3 months prior to radiographic progression. Emergent RAS mutations were associated with less favorable patient outcomes. Clinical trial information: NCT03401957 .